NO321835B1 - Process for the preparation of 4-hydroxy-2-oxopyran derivatives which can be used in the preparation of protease inhibitors, as well as intermediates in the process - Google Patents

Abstract

Disclosed is a novel process and novel intermediates to prepare [R-(R*,R*)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX) which is a protease inhibitor useful in treating humans infected with the HIV virus.

Description

1. The scope of the invention

The present invention relates to new methods for the production of hydroxylactones, and new intermediates for producing [R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy -2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX), which is a protease inhibitor useful in treatment of people infected with the HIV virus.

2. Description of Related Art

[R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl -2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX) can be prepared by the method described in international publications

WO 95/30670 and WO 94/11361.

J. Med Chem., 39(22), 4349 (1996) describes the cyclic ester (VI), but in the racemic form. This document also describes the transformation of the cyclic ester (VI) into the protease inhibitor (XIX), but by a different synthetic reaction route.

J. Am. Chem. Soc, 111, 3627 (1997) describes the amino compound (XVIII).

Tetrahedron Letters, 34(2), 277-280 (1993) describes a method for converting a p-hydroxycarbonyl compound into a ring similar to that of formulas (VI) and (CVI). The p-hydroxycarbonyl compound according to the prior art is a secondary alcohol, and the compound according to the present invention is a tertiary alcohol. The methods are also completely different in that the method according to Tetrahedron Letters cannot be applied to the tertiary alcohols (IV) and (CIV) according to the present invention.

J. Med. Chem., 39(23), 4630-4642 (1996) describes a method for preparing compounds similar to the compounds of formulas (VI) and (CVI), but in racemic form, from starting materials different from the materials used in the present invention, and by an unrelated method.

International publication WO 95/14012 describes a cyclic compound similar to the cyclic compounds (VI), (XVII) and (XXV) according to the present invention, but in racemic form. The method according to the present invention produces these compounds in optically pure form.

Summary of the invention

The present invention relates to (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid (IV) and pharmaceutically acceptable salts thereof.

The invention also relates to (6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2-one.

The invention also relates to [3a(R),6(R)]-5,6-dihydro-4-hydroxy-3-[1-(3-nitrophenyl)propyl]-6-[1-(2-phenyl)ethyl] -6-propyl-2H-pyran-2-one (XVII).

The invention further relates to (S)-methyl-3-(3-nitrophenyl)-pentanoate.

The invention also relates to [3a(R),6(R)]-5,6-dihydro-4-hydroxy-3-t(2)-1-(3-nitrophenylJpropenyl)-6-[1-(2-phenyl) ethyl]-6-propyl-2H-pyran-2-one.

The invention also relates to a method for producing the hydroxylactone of formula (CVI)

where Ri is:

C 1 -C 8 alkyl,

cyclohexyl,

phenyl,

-CH2-CH2~4»Ri-1 / where Ri_i is -OH (and protected forms thereof), -NH2 (and protected forms thereof),

-H,

-NH-CO-CH3,

-N(-CO-CH 3 ) 2 i

where R2 is:

C 1 -C 6 alkyl,

cyclohexyl,

phenyl,

-CH2~CH2-^R2-1 r where R2-i is -OH (and protected forms thereof), -NH2 (and protected forms thereof),

-H,

-NH-CO-CH3,

-N(-CO-CH 3 ) 2 i

which method comprises that:

(1) a salt of formula (CIV) is contacted with an acid to produce a free acid, (2) the free acid is extracted from the reaction mixture, (3) the free acid is contacted with an activator, (4) the free acid/activator reaction mixture is contacted with malonate monoester and a divalent metal, (5) contacting the reaction mixture from step (4) with an acid, (6) contacting the reaction mixture from step (5) with a base in the presence of a C 1 -C 4 alcohol, THF or

DMF.

The invention also relates to a method for producing the hydroxylactone of formula (CVI)

where Ri is:

C 1 -C 8 alkyl,

cyclohexyl,

phenyl,

-CH2-CH2-<t>Ri-i, where R1-1 is -OH (and protected forms thereof), -NHa (and protected forms thereof),

-H,

-NH-CO-CH 3 , -N(-CO-CH 3 ) 2 ;

where R2 is:

(VCe-alkyl,

cyclohexyl,

phenyl,

-CH2-CHj-<t»R2.1( where R2.! is -OH (and protected forms thereof), -NHa (and protected forms thereof),

-H,

-NH-CO-CH 3 , -N(-CO-CH 1 ) i ; which method comprises that: (1) the anion of formula (CIV) or the free acid form thereof is contacted with an activating agent, (2) the free acid/activating agent reaction mixture is contacted with malonate monoester and a divalent metal, (3) the reaction mixture from step (2) is contacted with an acid, (4 ) the reaction mixture from step (3) is contacted with a base in the presence of a C₁-C₂ alcohol, THF or

DMF.

Detailed description of the invention

The present invention relates to two new methods for the production of hydroxylactones, as well as new intermediate products for, after further reaction steps, to produce [R-(R*,R*) ] -N-[3-[I-[5,6-dihydro-4 -hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX), which is known as a protease inhibitor and which is applicable in the treatment of infected humans

with HIV.

Scheme A shows transformation of the ketone (I) to the corresponding ketoester (II), to the corresponding acid (III), to the corresponding salt (IV), to the corresponding ketoalcohol (V) and finally to the corresponding cyclic ester (VI ); see also Examples 1-4 and the preferred method, Example 18.

Scheme B shows transformation of 4-chlorothiophenol (VII) to the corresponding chloroether (VIII), to the corresponding biphenyl compound (IX); see also examples 5 and 6.

Scheme C shows the condensation of the biphenyl compound (IX) with the salt (IV) to give the ester ether (X), and the transformations of the ester ether (X) to the corresponding alcohol (XI) and to the corresponding aldehyde (XII). Also shown is the coupling of the optically pure nitroester (XIII) with the aldehyde (XII) to produce the corresponding nitroether (XIV); see also examples 7-10.

Scheme D shows the transformations of the nitroether (XIV) into the corresponding nitroketone (XV), into the corresponding nitroalcohol (XVI), into the corresponding nitro-a,p-unsaturated ester (XVII), into the corresponding amino compound (XVIII) and into the corresponding protease inhibitor (XIX); see also examples 11-15.

Scheme E shows the preparation of the optically pure nitroester (XIII) used in Scheme C. Scheme E shows the optical resolution of the racemic 1-(3-nitrophenyl)propanol (XX) to produce the corresponding optically pure 1-(3- nitrophenyl)propanol (XXI) and its transformation to the corresponding methyl sulfonate (XXII), to the corresponding diester (XXIII), to the corresponding nitro acid (XXIV) and to the corresponding optically pure nitroester (XIII); see also exhibits 1-5.

Scheme F shows an alternative, and preferred, reaction pathway for transformation of the cyclic ester (VI) to the corresponding nitro-a,p-unsaturated ester (XVII). The cyclic ester (VI) has been added to the m-nitrophenyl group to become

The 6(R)-olefin (XXV), see Example 16, which is hydrogenated with the appropriate catalyst to produce the reduced compound, the nitro-α,p-unsaturated ester (XVII), see Example 17. The

nitro-α,<p->unsaturated ester (XVII) is then transformed into the protease inhibitor (XIX), as discussed above.

Scheme G shows a method for producing optically pure hydroxylactones of formula (CVI). The procedure for the transformation of the salt of formula (CIV) to the hydroxylactone of formula (CVI) follows Examples 1-4 and 18. The hydroxyl and amino groups of the starting material (CI) can be protected, as is well known to those skilled in the art. These protecting groups can be removed at various places in the subsequent process steps by means of methods well known to those skilled in the art, or postponed until the end of the process where they will be removed to produce the desired product. It will be obvious to one skilled in the art that there are different ways to produce the optically pure (CIV). It is not important how the resolution according to Example 3, which produces the optically pure (CIV), is carried out. The invention here is the conversion of the optically pure (CIV) to the optically pure (CVI).

The acid (III) forms base addition salts when reacted with bases of sufficient strength. The pharmaceutically acceptable salts include both inorganic and organic bases. The pharmaceutical salts are preferred over the free acids because they produce compounds that are more water soluble and more crystalline. The preferred pharmaceutically acceptable salts include e.g. salts of the following bases: hydroxide, ammonia, tromethamine (THAM), 2-amino-2-(hydroxymethyl)-1,3-propanediol, (1R,2S)-norephedrine, (IS,2R)-norephedrine, ( R)-2-amino-2-phenylethanol, (S)-2-amino-2-phenylethanol, (R)-1-phenylethylamine and (S)-1-phenylethylamine. It is preferred that the salt is the (IR,2S)-norephedrine salt.

[R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl -2H-pyran-3-yl]propyl]phenyl]-5-(tri-fluoromethyl)-2-pyridinesulfonamide (XIX), the compound of Example 15, is known to be useful in the treatment of humans infected with HIV, see International publications WO 95/30670 and WO 94/11361. This compound inhibits retrovirus proteases and thus inhibits the replication of the virus. The compound is useful for inhibiting human retrovirus protease. The compound is useful in the treatment of human patients infected with a human

retroviruses, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) that result in acquired immunodeficiency syndrome (AIDS) and/or related diseases.

Patients to be treated will be those individuals who (1) are infected with one or more strains of a human retrovirus, as determined by the presence of either measurable viral antibody or antigen in serum, and (2) in the case of HIV, who have either an asymptomatic HIV infection or a symptomatic AIDS-defining infection, such as (a) disseminated histoplasmosis, (b) isopsoriasis, (c) bronchial and pulmonary candidiasis, including pneumocystis pneumonia, (d) non-Hodgkin's lymphoma, or (e ) Kaposi's sarcoma, and who are less than 30 years old; or who have an absolute CD4<+->lymphocyte count less than 500/mm<3> in the peripheral blood. Treatment will consist of maintaining an inhibitory level of the compound in the patient at all times.

The compound is useful for treating patients infected with human immunodeficiency virus (HIV) resulting in acquired immunodeficiency syndrome (AIDS) and related diseases. For this indication, these compounds can be administered orally, intranasally, transdermally, subcutaneously and parenterally (including intramuscularly and intravenously), in doses of 0.1 mg to 100 mg/kg body weight per day. It is preferred that the compounds are administered orally.

Those skilled in the art will know how to formulate the compound into suitable pharmaceutical dosage forms. Examples of dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.

When the compound is administered orally, an effective amount is from about 0.1 mg to 100 mg/kg body weight per day. It is preferred that the effective amount is from approx. 10 to 100 mg/kg body weight per day. It is more preferred that the amount is from approx. 30 mg to 90 mg/kg body weight. It is preferred that the compounds are administered 2-5 times daily, more preferably three times daily. It is preferred that the dose is from approx. 2700 mg/day to approx. 4500 mg/day.

Either solid or liquid dosage forms can be prepared for oral administration. It is preferred that the compounds are given in solid dosage form, more preferably as a capsule.

When the compounds are administered parenterally, they can be given by injection or by intravenous infusion. An effective amount is from approx. 0.1 mg to 100 mg/kg body weight per day. Parenteral solutions are prepared by dissolving the compounds in an aqueous vehicle, followed by filter sterilization of the solution before placing it in a suitable sealable container or ampoule. Parenteral suspensions are prepared in essentially the same way, with the exception that a sterile suspension is used and the compound is sterilized with ethylene oxide or a suitable gas before it is suspended in the vehicle.

The exact mode of administration, dose or frequency of administration will be readily determined by those skilled in the art and will depend on age, weight, general physical condition and/or other clinical symptoms specific to the patient to be treated.

Definitions and conventions

The definitions and explanations below are for the terms used throughout this document, including both the description and the requirements.

Definitions

All temperatures are in degrees Celsius.

TLC refers to thin layer chromatography.

HPLC refers to high pressure liquid chromatography; 4.6 x 250 mm Zorbax C-8 column, mobile phase A = methanol, mobile phase B = 6.5 g t-butylammonium hydroxide in water, pH to 4.0 with acetic acid, gradient from 65/35 A/B to 70/30 A/B over 20 min, then isocratic 70/30 A/B over 5 min, then gradient to 90/10 A/B over 2 0 min; flow rate is 1.0 ml/minute; UV detection at 254 nm.

THF refers to tetrahydrofuran.

DMF refers to dimethylformamide.

MTBE refers to methyl-t-butyl ether.

DMSO refers to dimethyl sulfoxide.

Salt water refers to a saturated, aqueous sodium chloride solution.

Chromatography {column and flash chromatography) refers to the purification/separation of compounds expressed by (support material, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are given in ppm (8) downstream from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are given in ppm (8) downstream from tetramethylsilane.

MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. [M + H] + refers to the positive ion of a parent atom plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast nuclear bombardment.

Ether refers to diethyl ether.

Pharmaceutically acceptable refers to the properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view, and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.

When solvent pairs are used, is the ratio between the solvents used volume/volume (v/v).

When the solubility of a solid material in a solvent is used, the ratio between the solid material and the solvent is weight/volume.

Compound refers to [R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)- 6-Propyl-2H-pyran-3-ylpropyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX).

Alkyl refers to C1-C4 alkyl, including both straight and branched chain isomers.

WL refers to ethyl and t-butyl.

Examples

Without further elaboration, it is assumed that a person skilled in the art, by applying the preceding description, can practice the present invention in its widest scope. The following detailed examples describe the way to prepare the various compounds and/or carry out the various methods according to the invention, and should only be understood as illustrative of the preceding description. Those skilled in the art will quickly find suitable variations of the procedures, both with regard to reactants and reaction conditions and techniques.

Production 1

Dissolution of ( ±)- 1-( 3- nitrophenyl) propanol ( XX) by conversion to ( S)- 1-( 3- nitrophenyl) propanol ( XXI) and ( R)- 1-( 3- nitrophenyl) propanol acetate

Celite-supported PS-30 lipase (Amano, 24 g) and isopropenyl acetate (22.00 mL, 0.20 mol) are added to (±)-1-(3-nitrophenyl)propanol (XX, 24.00 g, 0 .13 mol) in MTBE (240 mL). The mixture is stirred at 20-25 °C for 2 days. At the end of this time, the catalyst is removed by filtration, the catalyst cake is washed with ether, and the mixture is concentrated under reduced pressure to give an acetate-alcohol mixture. Separation of the mixture by silica gel chromatography gives (R)-1-(3-nitrophenyl)-propanol acetate (13.03 g), [a]D = +68.7° (ethanol, c = 1) , and (S)- 1-(3-nitrophenyl)propanol (10.7 g), [αJD = -33.0° (ethanol,

c = 1).

Manufacturing 2

( S )- 1-( 3- nitrophenyl) propanol mesylate ( XXII)

Diisopropylethylamine (1.07 g, 8.3 mmol) is added to a mixture of (S)-1-(3-nitrophenyl)propanol (XXI, Preparation 1, 1g, 5.5 mmol) in methylene chloride (20 mL). The mixture is cooled to -20 °C, and methanesulfonyl chloride (0.69 g, 6.02 mmol) is added. is set. The reaction mixture is kept at -20<*>C for 10 minutes and then at 0°C for 40 minutes. The reaction mixture is diluted with methylene chloride, sodium bicarbonate (5%) is added, and the phases are separated. The methylene chloride is evaporated to give the title compound, [α]D = -79.9° (ethanol, c = 1); TLC (silica gel GF, ethyl acetate/hexane, 20/80), Rf = 0.19; NMR (CDCl 3 , TMS), 0.96-1.01, 1.88-2.17, 2.89, 5.54-5.59, 7.57-7.62, 7.70-7.73 and 8.20-8.24 5.

Manufacturing 3

fS\- dimetvl- l- r1- t 3- nitrophenvl^ proovlImalonate fXXIII)

A solution of sodium ethoxide (1.0 M) is prepared by dissolving sodium metal (1.27 g, 0.055 mol) in absolute ethanol (55 mL). DietyImalonate (8.84 g, 0.055 mol) is added to this solution at 0 °C. (S)-1-(3-nitrophenyl)propanol mesylate (XXII, Preparation 2, 1.43 g, 5.5 mmol) is added dropwise to the solution of sodium malonate (6.4 mL, 6.4 mmol) at -20 °C . After 2 h at 20-25 °C, a further aliquot of sodium malonate (5 mL, 5.0 mmol) is added to the reaction mixture, which is then stirred overnight at 20-25 °C. The reaction mixture is concentrated and partitioned between ethyl acetate and hydrochloric acid (1 N ).The organic phase is separated and the solvent is removed to give a crude product which is chromatographed (silica gel; ethyl acetate/hexane, 10/90) to give the title compound, [<x]D = +19.4° (ethanol, c = 1); TLC (silica gel GF, ethyl acetate/hexane, 20/80), Rf = 0.48; NMR (CDCl 3 , TMS) 0.70-0.75, 0.96-1.00, 1.27- 1.32, 1.56-1.88, 3.37-3.45, 3.65-3.69, 3.86-3.96, 4.21-4.28, 7.44-7, 49, 7.54-7.57 and 8.08-8.11 8.

Manufacturing 4

( S )-( 3-nitrophenylpentanoic acid ( XXIV\

(S)-Dimethyl-1-[1-(3-nitrophenyl)propyl]malonate (XXIII, Preparation 3, 0.73 g, 2.26 mmol) is refluxed in hydrochloric acid (6 N, 10 mL) for 18 h. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phase is washed with water, separated and condensed to give the title compound, [α]o = 13.3° (methanol, c = 1); TLC (silica gel GF, acetic acid/ethyl acetate/hexane, 2/20/80), Rf = 0.46; NMR (CDCl 3 , TMS) 0.78-0.83, 1.59-1.82, 2.59-2.78, 3.07-3.17, 7.44-7.54 and 8.04- 8,10 8.

Manufacturing 5

f±)- 3-( 3- nitrophenyl)pentanoic acid methyl ester fxi11\

To a solution of (±)-3-(3-nitrophenyl)pentanoic acid (XXIV, 30.21 g, 135 mmol) in methanol (250 ml) is added concentrated sulfuric acid (0.6 ml). The resulting mixture is refluxed for 3 hours. On cooling, the mixture is partitioned between ethyl acetate and sodium bicarbonate (5% aqueous). The aqueous layer is separated and back-extracted with two further portions of ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound, TLC (silica gel GF) for acetic acid/ethyl acetate/hexane (2/20/80), Rf = 0.54, for ethyl acetate /hexane (20/80), Rf = 0.54; NMR (CDCl 3 , TMS) 0.80, 1.56-1.83, 2.55-2.75, 3.05-3.2, 3.57, 7.4-7.55 and 8.03- 8.12 6.

Production 6

( S\- 3-( 3- nitrophenyl^ pentanoic acid methyl ester fXIII>).

Following the general procedure of Preparation 5 and making non-critical variations, but starting with (S)-3-(3-nitrophenyl)pentanoic acid (XXIV, Preparation 4), the title compound is obtained.

Example 1

Ethyl- 3- hydroxy- 3-( 2- phenylethyl hexanoate t II)

To a solution of diisopropylamine (32.2 ml,

230 mmol) in tetrahydrofuran (240 ml) at -58 °C is added 2.63 M n-butyllithium in hexane (87.4 ml, 230 mmol) during

1 hour. Ethyl acetate (21.4 mL, 220 mmol) is then added and the reaction mixture is stirred for 1 h while cooling to

-70 °C. 1-Phenyl-3-hexanone (I, 35.2 g, 200 mmol) is added slowly over 30 minutes, and the reaction mixture is stirred for 1 hour. The reaction is stopped with aqueous ammonium chloride (100 ml), and the reaction mixture is heated to 20-25 °C. The mixture is then acidified with hydrochloric acid (4 M). The desired product is extracted with methyl t-butyl ether, dried over magnesium sulfate and concentrated to give the title compound, TLC, Rf = 0.71 (ethyl acetate/hexane, 30/70); NMR (CDCl 3 ) 7.28-7.12, 4.13, 3.60, 2.73-2.63, 2.50, 1.83-1.77, 1.58-1.53, 1, 41-1.36, 1.24 and 0.93 8; CMR (CDCI3) 173.0, 143.2, 128.5, 128.4, 128.3, 128.1, 125.8, 72.8, 60.6, 42.9, 41.3, 30, 1, 17.0, 14.6 and 14.2 5; MS (CI, ammonia) m/z (relative intensity) 282

(100), 264 (63), 247 (10), 194 (13), 172 (5), 159 (5).

Example 2

3- hydroxy- 3-( 2- phenylethyl) hexanoic acid ( 111 )

Ethyl 3-hydroxy-3-(2-phenethyl)hexanoate (II, Example 1, 200 mmol) is dissolved in methanol (423 mL), and 2 M sodium hydroxide (150 mL, 300 mmol) is added. The reaction mixture is stirred at 20-25 °C overnight. The methanol is removed, and the remaining aqueous mixture is acidified with hydrochloric acid (4 M). The desired product is extracted with methyl-t-butyl ether and dried over magnesium sulfate. The product is concentrated to give the title compound, TLC, Rf = 0.10 (ethyl acetate/hexane, 30/70); NMR (CDCl 3 ) 7.43-7.13, 2.77-2.62, 2.06, 1.87-1.76, 1.63-1.57, 1.45-1.31 and 0, 93 8; CMR (CDCI3) 176.9, 141.9, 128.4, 128.3, 125.9, 73.4, 42.7, 41.4, 40.9, 31.9, 17.0 and 14, 5 8; MS (Cl, ammonia) m/z (relative intensity) 254 (100), 236 (28), 218 (3), 194 (3), 159 (5).

Example 3

( R)- 3- hydroxy- 3-( 2- phenylethyl^ hexanoic acid. in lR. 2S^- norephedrine salt ( IV)

3-Hydroxy-3-{2-phenylethyl)hexanoic acid (III, Example 2, 2.83 g, 11.97 mmol, adjusted for methyl-t-butyl ether) is dissolved in acetonitrile (15 mL). (IR,2S)-norephedrine (910 mg, 5.99 mmol, 0.5 equiv) is added and the mixture is stirred overnight at 20-25 °C. After approx. After 1 hour, the product begins to precipitate. The following morning, the slurry is cooled to 0 °C for 1 hour before filtering to collect the hydroxy acid salt. The filter cake is washed with acetonitrile (9 ml, cold) and dried under reduced pressure and with heat to give the desired product.

This material (approx. 1.5 g) is suspended in acetonitrile (21 ml) and heated to 70 °C for 30 minutes. The resulting solution is gradually cooled to 20-25 °C as the product precipitates. After 2 hours at 20-25 °C, the product is collected by vacuum filtration, washed with acetonitrile (21 ml) and dried at 20-25 °C under reduced pressure.

This material is resuspended in acetonitrile

(21 ml) and heated at 70 °C for 30 minutes. The resulting solution is gradually cooled to room temperature, 20-25 °C, when the product precipitates. After 2 hours at 20-25 °C, the product is collected by vacuum filtration, washed with acetonitrile (21 ml)

and dried at 20-25 °C under reduced pressure to give the title compound, m.p. « 113-117 °C; NMR (methanol) 7.41-7.08, 5.18, 4.98, 3.15, 2.65-2.60, 2.34, 1.79-1.73, 1.56-1, 52, 1.43-1.37, 1.06 and 0.925; CMR (methanol) 181.4, 144.6, 142.2, 130.2-129.3, 127.6, 127.1, 74.5, 73.9, 54.0, 46.4, 43, 6, 43.4, 31.9, 31.9, 18.6, 15.7 and 12.9 8; MS (CI, ammonia) m/z (relative intensity) 388 (25), 303 (15), 254 (30), 236 (7), 152 (100); [«]£ = 16 (C = 1.0, methanol).

Example 4

( 6R)- 5. 6- dihvdro- 4- hvdroksv- 6- f 1- f 2- phenvl) etvl1- 6- propvl- 2H- pvran- 2- one ( VI)

(R)-3-Hydroxy-3-(2-phenylethyl)hexanoic acid, (IR,2S)-norephedrine salt (IV, Example 3, 81 g, 209 mmol) is converted to the free acid, (R)-3-hydroxy- 3-(2-phenylethyl)hexanoic acid by slurrying the salt in ethyl acetate (810 ml) and adding hydrochloric acid (1M, 810 ml). The free acid is extracted with ethyl acetate, and the ethyl acetate layer is collected and concentrated to an oil. The free acid is then redissolved in tetrahydrofuran (490 ml), and the solution is cooled to -10 °C. Carbonyldiimidazole (37.3 g, 230 mmol) is added and the reaction mixture is stirred cold for 2 hours. Monoethylmalonate magnesium salt (65.9 g, 230 mmol) is added and the reaction mixture is gradually warmed to 20-25 °C with stirring overnight. The reaction is quenched with hydrochloric acid (1 M, 490 ml) and the organic layer is collected. The organic layer is washed with a sodium bicarbonate solution and concentrated to 294 ml containing (R)-ethyl-S-hydroxy-7-phenyl-5-propylheptanoate (V). A solution of sodium hydroxide (0.5 M, 460 mL, 230 mmol) is added to the concentrated solution and the resulting cloudy mixture is stirred at 20-25 °C overnight. Methyl t-butyl ether is added and the aqueous layer is collected. The aqueous phase is acidified with hydrochloric acid (4 M), and the product is extracted with methyl-t-butyl ether. The methyl t-butyl ether layer is dried over sodium sulfate and concentrated to give the title compound, TLC, Rf = 0.22 (ethyl acetate/hexane, 50/50); NMR (CDCl 3 ) 7.29-7.13, 3.39, 2.70, 2.71-2.62, 1.98-1.93, 1.74-1.66, 1.45-1, 34 and 0.93 8; CMR (CDC13) 176.89, 167.5, 140.4, 128.6, 128.4, 128.2, 128.2, 126.3, 83.2, 60.1,

47.1, 44.3, 40.7, 40.4, 29.6, 16.8 and 14.5 8; MS (Cl, ammonia) m/z (relative intensity) 278 (100), 254 (15), 236 (15), 217 (5), 195 (5), 159 (3).

Example 5

M- phenylphenoxyl ( 4- chlorothiophenoxylmethane ( vim

For a sieving of paraformaldehyde (36.24 g,

1.21 mol, 1.58 eq.) in toluene (243 ml) at 22 °C is added aqueous hydrogen bromide (48.5% by weight, 652 ml, 5.86 mol,

7.68 eq.) with an endotherm to 18 °C. The resulting biphasic solution is heated to 40 °C and a solution of 4-chlorothiophenol (VII, 138.81 g, 0.960 mol, 1.26 eq) in toluene (116 mL) is added over half an hour under maintaining the temperature at 40-43 °C, and rinsed with toluene (50 ml). The mixture is then heated to 50 °C and stirred for 1 hour. The mixture is cooled to 10 °C, the phases are separated, and the aqueous phase is washed with toluene (250 ml). The combined organic phases are treated with ice water (500 mL), hexanes (350 mL), and the phases are separated. The aqueous phase is then washed with toluene (200 mL), and the combined organic phases are dried over magnesium sulfate and concentrated to give crude bromomethylthio-4-chlorobenzene (268.01 g), NMR 7.43, 7.34, 4.79 8; CMR 134.37, 132.05, 131.78, 129.46, 37.32 8; HRMS (El<+>) calcd for C7H6BrClS = 235.9063, found = 235.9063.

To a solution of 4-phenylphenol (129.91 g,

0.763 mol, 1.00 eq.) in DMF (400 mL) at -10 °C is added a solution of potassium t-butoxide in THF (20 wt%, 429.40 g, 0.765 mol, 1.00 eq.) , followed by THF (50 mL), maintaining the temperature below 5 °C. The mixture is concentrated to 557 g net weight and DMF (33 ml) is added followed by crude bromomethylthio-4-chlorobenzene, prepared above, with a free exotherm from 22 to 70 °C. The crude bromomethylthio-4-chlorobenzene is rinsed with DMF (50 mL) and the resulting slurry is stirred at 80 °C for 1/2 hour. The mixture is cooled to 22 °C and hexanes (400 mL) followed by water (500 mL) are added. The precipitate is collected by vacuum filtration and washed with water (1500 ml) and methanol (300 ml) and dried in a stream of nitrogen to give a solid (251.25 g). The solid material is dissolved in methylene chloride

(1 1) and dried over magnesium sulfate and washed with methylene chloride {200 ml). A concentration at constant volume (1300-1800 ml) is then carried out with the addition of a total of 1.35 1 methanol and with the final result 1344 g net weight. The resulting precipitate is collected at 20-25 °C by vacuum filtration, washed with methanol (1 L) and dried at 65 °C under reduced pressure to give the title compound, m.p. = 99-101 °C; TLC (Rf 0.64, ethyl acetate/hexanes, 1/9); HPLC (rt) = 9.67 min.; NMR (CDCl 3 ) 7.55-6.99 and 5.44 8; CMR (CDC13) 155.99, 140.52, 135.28, 133.48, 132.06, 129.18, 128.75, 128.24, 126.90, 126.80, 116.34, 73, 15 8; MS (Cl, NH3) m/z (relative intensity) 346 (1.7), 344 (3.5), 328 (3.8), 326 (8.1), 201 (11), 200

(100).

Example 6

l-chloromethoxy-4-phenylbenzene (IX)

A solution of sulfuryl chloride (73 .32 g, 543.2 mmol, 1.01 eq.) in methylene chloride (150 mL) while maintaining the temperature below 23 °C for 8 min. The mixture is stirred at 20°C for 11 minutes and then cooled to 3°C. A mixture of the cyclowitch

(60.7 mL, 599 mmol, 1.11 eq.) in methylene chloride (100 mL) is added over 10 min at 3-5 °C, then warmed to 19 °C and stirred for 10 min. The mixture is concentrated to 600 ml total volume, and hexanes (500 ml) are added. The mixture is concentrated to 500 mL, and hexanes (300 mL) are added. The resulting slurry is concentrated to 500 mL and pentane (1.3 L) is added. The slurry is cooled to -50 °C and the precipitate is collected by vacuum filtration and washed with pentane (700 mL) at -30 °C and dried to give a solid (115.28 g). A portion (110.34 g) of the solid material is dissolved in methylene chloride (200 ml). Hexanes (1 L) are added and the mixture is concentrated to 949 g. Hexane (200 ml) is added and the mixture is concentrated to 589 g. Hexane (500 ml) is added, the slurry is cooled to -30 °C, the precipitate is collected by vacuum filtration, washed with hexane (300 mL) and dried to give the title compound, m.p. 67-70 °C; TLC, R f =

0.68 (ethyl acetate/hexanes, 8/92); HPLC rt = 6.45 min.; NMR 7.80-7.13 and 5.89 6; CMR < CDCl3 ) 155.03, 140.34, 136.49, 128.78, 128.35, 127.10, 126.88, 116.39 and 77.16 5; HRMS (EI<+>) calculated for C13HnC10 = 218.0498, found - 218.0493.

Example 7

( R )- i 4- phenylphenoxy) methyl- 3- f 2- phenylphenoxy)- 3- f( 4- phenylphenoxy)- methoxylhexanoate ( X)

To a slurry of (R)-3-hydroxy-3-(2-phenylethyl)-hexanoic acid-(-)-norephedrine salt (IV, Example 4, 25.04 g,

64.62 mmol) in water (185 ml) and MTBE (185 ml) at 20-25 °C is added aqueous hydrochloric acid (37.5% by weight, 7.51 g, 77.24 mmol,

1.20 eq.), which adjusts the pH from 8.04 to 1.30. The phases are separated, and the aqueous phase is washed with MTBE (185 ml). The organic phases are dried over magnesium sulfate and concentrated. To the concentrate are then added toluene (77 ml), N,N-diisopropylethylamine (96 ml, 551 mmol, 8.53 eq.) and 1-chloromethoxy-4-phenylbenzene (IX Example 6, 71.88 g, 328.68 mmol , 5.09 eq). The mixture is then heated to 110 °C and stirred at 110-117 °C for 5 hours. The mixture is cooled to 65 °C and methanol (800 mL) is added. The resulting slurry is cooled to

-30 °C, and the product is collected by vacuum filtration, washed with methanol (200 ml) and dried to give a crude product. An analytical sample is obtained by chromatography (ethyl acetate/hexanes), followed by crystallization to give the title compound, m.p. = 104.0-105.5 °C; TLC, Rf = 0.50 (15% ethyl acetate/hexanes); HPLC rt « 13.8 min.; NMR (CDCl 3 ) 7.51-7.04, 5.78, 5.32, 2.75, 2.64-2.58, 2.03-1.97, 1.78-1.72, 1, 41-1.28 and 0.86 6; CMR (CDC13) 169.38, 157.14, 156.14, 142.04, 140.71, 140.41, 135.85, 134.56, 128.75, 128.68, 128.35, 128, 29, 128.09, 126.97, 126.81, 126.73, 125.78, 116.13, 87.34, 85.20, 80.40, 41.19, 38.80, 38.61, 29.73, 16.74, 14.35 5; MS (Cl, NH3) m/z (relative intensity) 620 (1.7), 619 (7.8), 618 (19), 418 (13), 266

(100); [ a]% = -4 (C = 1.0, methylene chloride).

Example 8

( R )- 3-( 2- phenylethyl)- 3- r f4- phenylphenoxy) methoxy 1 hexanol ( XI)

To a slurry of crude (R-)-(4-phenylphenoxy)-methyl-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanoate (X, Example 7, 56.5 wt%, 49 .32 g, 46.38 mmol in toluene (500 ml) is added a solution of diisobutylaluminum hydride in toluene (1.52 M, 85 ml, 129.2 mmol, 2.79 eq.) while maintaining the temperature at -20 °C . The mixture is slowly warmed to 1 °C over 2.5 h and then stirred for 1/2 h. Acetone (8.0 mL, 108.5 mmol, 2.34 equiv) is added and the mixture is transferred by cannula at 18 °C in a solution of citric acid monohydrate (136 g, 647.2 mmol, 14.0 equiv) in water (433 mL) with controlled exotherm to 28 °C and rinsed with toluene (100 mL).The mixture is stirred at 20 -25 °C for 1.5 hours, and undissolved material is removed by vacuum filtration and washing with toluene. The phases are separated in the filtrate, and the aqueous phase is washed with toluene (2 x 300 ml). The organic phases are dried over magnesium sulfate and then washed with aqueous sodium hydroxide (0.5 M, 2 x 500 ml) The organic phases is concentrated to 137 g net weight, and methanol (250 ml) is added. The resulting slurry is concentrated and methanol (250 mL) is added. The mixture is concentrated again and methanol (250 mL) is added. The slurry is cooled to -60 °C, and the undissolved material is removed by filtration. The filtrate is concentrated to 60 g net weight, hexane (500 ml) is added, and the mixture concentrated to 22 g net weight. Hexane (500 mL) is added and the mixture is concentrated again to 40 g net weight. Methylene chloride (25 mL) is added, followed by slow addition of hexane (500 mL) and pentane (250 mL) while cooling to -55 °C. The product is collected by vacuum filtration, washed with pentane (200 ml) and dried in a stream of nitrogen to give the desired product. An analytical sample is obtained by chromatography (ethyl acetate/hexane), followed by crystallization (methylene chloride/hexane) to give the title compound, m.p. - 49-53 °C; TLC, Rf = 0.14 (15% ethyl acetate/hexane); HPLC rt = 9.18 min.; NMR (CDCl 3 ) 7.56-7.07, 5.36, 3.76-3.74, 2.63-2.58, 1.94-1.88, 1.70-1.65, 1, 38-1.30, 0.93 8; CMR (CDCI3) 157.05, 142.25, 140.73, 134.68, 128.70, 128.42, 128.29, 128.21, 126.76, 125.85, 116.07, 87, 05, 81.85, 58.89, 38.77, 38.60, 38.23, 29.90, 17.04, 14.62 8; MS (Cl, NH 3 ) m/z (relative intensity) 423 (2.3), 422 (9.9), 252 (100); [a]£ = 6 (C = 1.0, methylene chloride) .

Example 9

( R \- 3 -( 2- phenylethyl)- 3- r( 4- phenylphenoxyImethoxy1hexanal fXII)

To a mixture of crude (R)-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanol (XI, Example 8, 91.1 wt%, 15.40 g, 34.68 mmol) in methylene chloride (47 mL) at 0 °C is added a solution of potassium bromide (0.4057 g, 3.409 mmol, 0.098 eq.) and sodium bicarbonate (1.557 g, 18.53 mmol, 0.53 eq.) in water (20, 5 mL), followed by 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy, free radical (0.3060 g, 1.776 mmol, 0.051 equiv). Aqueous sodium hypochlorite (13.4% (w/v, 26.6 ml,

47.88 mmol, 1.38 equiv.) is then added using a syringe pump over the course of 1 hour while maintaining the temperature at 1-5 °C. A solution of sodium thiosulfate pentahydrate (0.5182 g, 2.088 mmol, 0.0602 equiv) in water (14 mL) is then added. The phases are separated at 0 °C, and the aqueous phase is washed with 2 x 50 ml of methylene chloride. The organic phases are immediately filtered through magnesol (50.25 g) and rinsed through with methylene chloride (400 ml). The extracts are concentrated to an oil (30 g) and hexane (500 ml) is added. The mixture is concentrated to 250 g net weight, and hexane (100 ml) is added. The mixture is concentrated to 186 g net weight, and pentane (300 ml) is added. The resulting slurry is cooled to

-50 °C, and the desired product is collected by vacuum filtration, washed at -50 °C with pentane (100 ml) and dried to give a solid, analytically pure title compound, m.p. = 47.0-48.5 °C; TLC, Rf = 0.41 (ethyl acetate/hexane, 10/90); HPLC rt = 10.95 min.; NMR (CDCl 3 ) 9.79, 7.53, 7.40, 7.26, 7.20-7.08, 5.40, 2.67, 2.65-2.56, 1.99, 1, 76, 1.38, 0.93 5; CMR (CDC13) 201.83, 156.90, 141.69, 140.68, 134.82, 128.72, 128.47, 128.29, 128.24, 126.77, 125.99, 116, 03, 87.19, 80.36, 50.14, 39.21, 39.14, 29.74, 16.86, 14.45 8; MS (Cl, NH 3 ) m/z (relative intensity) 420 (3.5), 220 (100); [a]£ = 14 (C = 1.0, methylene chloride) . Example 10 ( 3S ) ( 7R )- 4- carbomethoxy- 3-( 3- nitrophenyl)- T - t 2- phenylethyl)-7-ff4- phenvlphenocBy) methoxyl decan- 5-ol fblandin<g> of diastereomers at C- 4 and C- 5) fXIV) To a mixture of (S)-methyl-3-(3-nitrophenyl)pentanoate, also known as (S)-3-(3-nitrophenyl)pentanoic acid methyl ester (XIII, Preparation 6, 3, 78 g, 15.932 mmol) in THF (55 ml) at -80 °C is added a solution of sodium hexamethyldisilazide in THF (0.935 M, 17.5 ml, 16.36 mmol, 1.027 equiv.) over 7 minutes under maintaining the temperature at -80 to -85 °C. The resulting mixture is then warmed to -74°C and stirred at -74 to -76°C for 18 minutes. The mixture is cooled to -90 °C, and a solution of (4R)-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanal (XII, Example 9, 6.50 g, 16.147 mmol, 1.013 equiv.) in THF is added over 10 minutes while maintaining the temperature at -85 to -90 °C and rinsed with THF (20 mL). The mixture is then heated to -71 °C, and saturated aqueous ammonium chloride solution

(90 mL) is added, followed by water (90 mL) and MTBE (90 mL), and the mixture is heated to 20-25 °C. The phases are separated, and the aqueous phase is washed with MTBE (90 ml). The extracts are dried over magnesium sulfate and concentrated to an oil. An analytical sample is obtained by chromatography (ethyl acetate/hexanes) to give the title compound, TLC, Rf - 0.16, 0.24 (ethyl acetate/hexanes, 10/90); HPLC rt = 12.52, 12.68, 12.97 min.; MS (electrospray, sodium acetate) m/z (relative intensity) 662.5 (100).

Example 11

(3S)

A solution of (3S),(7R)-4-carbomethoxy-3-(3-nitro-phenyl)-7-(2-phenylethyl)-7-[(4-phenylphenoxy)methoxy]decan-5-ol (XIV , Example 10, 11.12 g, 79.0 wt%, 13.73 mmol) in methylene chloride (530 mL) is added to a ground mixture of pyridine-chlorochromate (16.099 g, 74.685 mmol, 5.44 eq.), sodium acetate (6.984 g, 85.14 mmol, 6.20 eq.) and florisil (5.181 g) while maintaining the temperature lower than 11 °C. The mixture is heated to 21 °C and stirred at 20-25 °C for 20 hours. The resulting slurry is filtered through magnesol (47.7 g) and rinsed with methylene chloride (375 mL). The filtrate is concentrated to an oil. An analytical sample of the title compound is obtained by chromatography (ethyl acetate/hexanes): TLC, Rf - 0.34 (ethyl acetate/hexanes, 10/90); HPLC rt = 13.02, 13.23 min.; NMR (CDCl 3 ) 8.05-8.01, 7.60-7.00, 5.37, 5.21, 4.03, 3.94, 3.75, 3.58-3.43, 3, 39, 2.96, 2.78-1.37, 1.20, 0.91, 0.71-0.61 8; CMR (CDC13) 200.89, 200.60, 168.29, 167.81, 157.10, 157.05, 148.38, 148.30, 143.58, 143.32, 141.99, 141, 93, 140.73, 140.69, 135.29, 135.01, 134.78, 129.38, 129.23, 128.75, 128.45, 128.36, 128.23, 126.77, 125.91, 125.80, 122.96, 122.80, 122.04, 122.00, 116.16, 87.14, 86.92, 80.93, 80.44, 66.34, 65, 92, 52.79, 52.35, 49.02, 48.62, 46.28, 46.20, 38.70, 38.51, 38.43, 37.99, 30.10, 29.52, 26.92, 26.71, 16.64, 16.39, 14.39, 14.16, 11.81, 11.58; MS (Cl, ammonia) m/z (relative intensity) 656 (2.8), 655 (6.1), 136 (100).

Example 12

( 3S).( 7R)- 4- carbomethoxyv- 7- hydroxy- 3- f3- nitrophenyl)- 7- f2-phenylethyHdecan- 5- one (mixture of diastereomers at C- 4) f XVI)

To a mixture of (3S),(7R)-4-carbomethoxy-3-(3-nitrophenyl)-7-(2-phenylethyl)-7-[(4-phenylphenoxy)methoxy]decan-5-one (XV, example 11, 9.14 g, 83.7 wt%, 11.995 mmol) in THF (20 ml) at 23 °C is added a solution of sulfuric acid in methanol (0.524 M, 20 ml, 10.48 mmol, 0.87 equiv .). The mixture is allowed to stand at 23 °C for 22 h, and then a solution of sodium bicarbonate (3.52 g, 41.90 mmol, 3.49 eq.) in water (50 mL) is added, followed by MTBE (50 mL) . The phases are separated, and the aqueous phase is washed with MTBE (30 ml). The combined organic phases are washed with aqueous sodium hydroxide (0.5 M, 2 x 50 mL) at 5 °C, then water (2 x 10 mL), then twice with a mixture of saturated aqueous ammonium chloride (15 mL) and water (35 ml). The organic phases are dried over magnesium sulfate and concentrated to an oil. An analytical sample of the title compound is obtained by chromatography (ethyl acetate/hexanes): TLC, Rf = 0.39 (ethyl acetate/hexanes, 25/75); HPLC rt = 8.15, 8.50 min.; NMR (CDCl 3 ) 8.15-7.85, 7.48-7.01, 3.99, 3.92, 3.78, 3.50-3.39, 3.38, 3.32-1, 21, 0.82 and 0.74-0.67 8; CMR (CDCI3),

205/20, 204.99, 168.00, 167.46, 148.38, 143.10, 142.04, 141.97, 135.23, 134.99, 129.47, 129.33, 128, 46, 128.41, 128.28, 128.18, 125.85, 122.82, 122.58, 122.17, 73.83, 73.49, 66.63, 66.36, 52.92, 52.50, 50.79, 50.60, 46.25, 46.17, 41.57, 41.01, 40.83, 30.03, 29.60, 26.95, 17.05, 16, 90, 14.55, 14.43, 11.74 and 11.47 6.

Example 13

r 3a f RI, 6 i mi - 5. 6- dihydro- 4- hvdroksv- 3- r 1- f 3- nitrof envl) - propvn- 6- r 1- f 2- phenvl) ethyl1- 6- propvl- 2H - pvran- 2- on fxvil)

A solution of aqueous sodium hydroxide (1 M,

11.4 ml, 11.4 mmol, 1.89 eq.) in methanol (35 ml) at 4 °C is added to crude (3S),(7R)-4-carbomethoxy-7-hydroxy-3-(3- nitrophenyl)-7-(2-phenylethyl)-decan-5-one (mixture of diastereomers at C-4) (XVI, Example 12, 73.3 wt%, 3.740 g, 6.018 mmol and rinsed with methanol (45 mL) while maintaining the temperature below 5 °C. The mixture is stirred vigorously to dissolve the bulk of the crude oil and then stirred moderately at 0-5 °C for 67 hours. The mixture is cooled to -5 °C and hexanes (90 mL) are added . The phases are separated at < 5 °C and the organic phase is washed at < 5 °C with a mixture of methanol (50 ml) and water (7 ml). The pH of the combined aqueous phase is adjusted from 12.55 to 6.24 at < 5 °C with acetic acid (1.52 g, 25.31 mmol, 4.21 equiv). The aqueous phase is concentrated, extracted with methylene chloride (2 x 40 mL), dried over magnesium sulfate and concentrated to give a crude product . To a sample of the crude product (0.401 g) is added ether (1.0 mL). The resulting slurry is cooled to -30 °C, and the precipitate collected by vacuum filtration, washed with cold ether and dried in a stream of nitrogen to give the title compound, TLC, Rf = 0.49 (ethyl acetate/hexanes, 1/1); HPLC rt =

6.93 min.; NMR (CDCl 3 /CD 3 OD, 1/1) 8.08, 7.80, 7.56, 7.22, 7.07-6.88, 3.98, 3.33-3.30, 2.50- 2.37, 1.92-1.70, 1.58-1.50, 1.22-1.14, 0.76 and 0.72 8; CMR (CDCI3/CD3OD, 1/1) 169.05, 166.66, 148.66, 147.79, 141.99, 135.30, 129.21, 129.02, 128.70, 126.55, 123.51, 121.23, 105.13, 81.39, 42.58, 40.39, 40.09, 36.76, 30.38, 24.95, 17.44, 14.54 and 13, 04 8.

Example 14

f 3ot( IO . 6( R)- 3 f l-( 3- aminophenvl) propvl 1 - 5, 6- dihydro- 4- hvdroxv-6- r 1- f 2- phenvl) ethyl1- 6- propvl- 2H- Pvran- 2- on t XVI11)

To a solution of [3a{R),6(R)]-5,e-dihydro^-hydroxy-S-t 1-(3-nitrophenyl)propyl]-6-[1-(2-phenyl)ethyl]-6 -propyl-2H-pyran-2-one (XVII, Example 13, 0.6993 g, 1.651 mmol) in THF (50 mL) is added palladium-on-carbon (5%, 50% water, 0.2574 g, 0 .06048 mmol, 0.0366 eq.)" and the mixture is hydrogenated at 3.5 kg/cm<2> on a Parr shaker for 21 hours. Celite (2.07 g) is added and the catalyst is removed by vacuum filtration and rinsed with THF. The filtrate is concentrated to give the title compound, TLC, Rf = 0.45 (ethyl acetate/hexanes, 1/1); HPLC rt = 5.18 min.

Example 15

f R-( R*. R* ) 1- N- f 3- r 1- r 5. 6- dihydro- 4- hydroxy- 2- oxo- 6-(2-phenvletyl)- 6- propvl- 2H- pvran - 3- vlIpropyl1phenyl1- 5-( trifluoro-methyl) - 2- pyridinesulfonamide fXIX)

To a mixture of [3a(R),6R]-3-[1-(3-aminophenyl)-propyl]-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]- 6-propyl-2H-pyran-2-one (XVIII, Example 14, crude 0.555 g,

1.378 mmol, based on the title compound XIX) in methylene chloride (3.10 mL), DMSO (0.100 mL, 1.409 mmol, 1.02 equiv) and pyridine (0.56 mL, 6.92 mmol, 5.02 equiv) is added to the crude mixture of 5-trifluoromethyl)-2-pyridinesulfonyl chloride in methylene chloride, prepared above (5.23 ml, approx. 2.3 mmol, based on thiol, approx.

1.7 eq.) at -25 to -30 °C over 2 h, followed by titration with the 5-(trifluoromethyl)-2-pyridinesulfonyl chloride mixture to an HPLC endpoint of 1.4 area percent remaining [3a(R ),6R]-3-[1-(3-aminophenyl)propyl]-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2 -on (XVIII, example 14). Aqueous hydrochloric acid (1 M, 6.2 mL, 6.2 mmol, 4.50 equiv) and ethyl acetate (5.2 mL) are added and the phases are separated. The aqueous phase is washed with methylene chloride (10 mL), and the combined organic phases are dried over magnesium sulfate and concentrated. The concentrate is applied to a silica gel column (9.76 g silica gel) packed with ethyl acetate/hexanes (10/90), and the product is eluted with the following mixtures of ethyl acetate in hexanes (50 ml 10%, 100 ml 20%, 100 ml 30% and 50 ml 40%).

The eluent is combined and concentrated to an oil using ethyl acetate. Ethyl acetate (5.2 ml) is added, and the product is precipitated by slow addition of heptane (15 ml). The resulting slurry is cooled to -30 °C and the precipitate collected by vacuum filtration, washed at -30 °C with a mixture of ethyl acetate (1 ml) and heptane (4 ml) and dried in a stream of nitrogen to give the title compound, m.p. = 86-89 °C; TLC, Rf = 0.66 (ethyl acetate/hexane, 50/50); NMR (CD 3 OD) 8.94, 8.19, 8.02, 7.25-6.97, 3.93, 2.68-2.52, 2.15-2.09, 1.96-1, 64, 1.33, 0.88 and 0.83 8; CMR (CD30D) 169.9, 167.0, 161.6, 148.1, 147.6, 142.8, 137.7, 137.0, 130.1, 129.5, 129.3, 127, 0, 126.1, 124.2, 122.6, 120.3, 106.2, 81.9, 43.6, 40.5, 40.5, 37.4, 30.9, 25.8, 17.9, 14.7 and 13.3 8; MS (Cl, ammonia) m/z (relative intensity) 621 (1.7), 620 (5.4), 604 (1.1), 603 (3.4), 411 (12), 394 (12) , 148 (100); IR (mull) 1596, 1413 1359, 1326, 1177, 1149, 1074 and 720 cm"<1> (same solid state form as the reference).

Example 16

r 3a( R), 6( R) 1- 5, 6- dihydro- 4- hydroxy- 3- r 13 - nitrophenyl)-propenyl1- 6- fl-(2- phenyl) ethyl1- 6- propvl- 2H- pvran - 2- on fXXV, main component) oa r 3a( R\. 6R1 - 5. 6- dihydro- 4- hydroxyv- 3- r f E)-1-( 3- nitrophenylipropenyl1- 6- rl-( 2- phenylletvl1- 6 - propvl- 2H- pyran-2- one fXXV, bicomponent)

(6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2-one (VI, Example 4, 50.0 g, 187 mmol) is combined with m-nitropropiophenone (33.5 g, 187.2 mmol) and 375 mL of THF. Add pyridine (31.0 mL, 374 mmol), and the resulting mixture is stirred and cooled to less than -5 °C. A solution is prepared by adding titanium tetrachloride (31 mL, 280 mmol) to 80 mL of toluene, and this solution is added to the mixture in a controlled manner to maintain the reaction temperature below 10 °C. Toluene (15 ml) is used as a rinse agent in the titanium tetrachloride solution, and at the end of this addition, the reaction mixture is heated to between 35 and 45 °C and maintained in this range for approx. 16 hours. The reaction mixture is cooled to 0 °C and water (200 mL) is added in a single portion. This mixture is stirred until all solid material is dissolved. The mixture is heated to at least 15°C and then transferred to a separatory funnel using water (250 mL) and ethyl acetate (500 mL) to dilute the mixture. The aqueous layer is separated, removed, extracted with ethyl acetate (150 mL) and discarded. The primary organic layer is washed sequentially with hydrochloric acid (IN, 2 x 150 mL), water (150 mL), and saturated sodium bicarbonate (150 mL). Each wash solution is extracted with the ethyl acetate extract (150 ml) before being discarded. At this point the primary organic layer and extract are combined and concentrated under reduced pressure to give a concentrate. The concentrate is then dissolved in methylene chloride (350 ml). This solution is extracted with a total of 500 ml of 1 N sodium hydroxide (4 x 50 ml, then 3 x 100 ml). The combined aqueous extracts are washed with a total of 500 ml of methylene chloride (4 x 50 ml, then 3 x 100 ml) and then treated with hydrochloric acid (3 N, 150 ml). The acidified mixture is extracted with methylene chloride (400 mL, then 6 x 100 mL), and the combined organic extracts are washed with water (200 mL) and then brine (200 mL). After subsequent drying with anhydrous sodium sulfate, the mixture is filtered through a pad of magnesol and then concentrated under reduced pressure to give the mixture of the title compounds, TLC, Rf - 0.18 for (Z) isomer, 0.28 for (E) isomer ( ethyl acetate/hexane, 1/1); CMR (CDC13) 166.93, 166.53, 148.27, 142.53, 142.39, 140.96, 132.23, 132.12, 131.82, 131.74, 129.87, 129, 12, 128.55, 128.14, 126.16, 121.67, 120.56, 101.09, 81.77, 39.78, 35.23, 29.73, 16.91, 15.75, 15.69 and 14.23 8; MS (Cl + NH 3 ) m/z (relative intensity) 439 (100), 422 (18), 409 (9), 392 (9), 278 (9), 194 (10), 136 (9).

Example 17

f 3of R). 6( Rn- 5. 6- dihydro- 4- hvdroxv- 3- f1-( 3- nitrophenvl\-propvl1- 6Tr l - t 2- phenvl) etvn- 6- propvl- 2H- pvran- 2- one f XVII \

[ 3a (R),6{R)-5,6-dihydro-4-hydroxy-3-[(Z)-1-(3-nitrophenyl)propenyl]-6-[1-(2-phenyl)ethyl] -6-propyl-2H-pyran-2-one (XXV, Example 16, 4.24 g, 10 mmol) and [{1,5-cyclooctadiene)-rhodium(I)-1,2-bis-{2R, 5R)-Dimethylphospholano)benzene]tetrafluoroborate (6.0 mg, 0.01 mmol) is combined under an inert atmosphere and dissolved in 20 mL of deoxygenated methanol. The atmosphere is replaced with hydrogen at a pressure of 5.6 kg/cm<2> or higher, and

the reaction mixture is heated to 55 °C and stirred for 24 hours. At the end of this period, the reaction mixture is cooled to 20-25 °C, and hydrogen is replaced with an inert atmosphere. The reaction mixture is concentrated under reduced pressure and the residue crystallized from a methanol/water mixture (3/1) to give the title compound, TLC, Rf = 0.49 (ethyl acetate/hexanes, 1/1); HPLC rt = 6.93 min.; NMR (CDCl 3 /CD 3 OD, 1/1) 8.08, 7.80, 7.56, 7.22, 7.07-6.88, 3.98, 3.33-3.30, 2.50- 2.37, 1.92-1.70, 1.58-1.50, 1.22-1.14, 0.76 and 0.72 6; CMR (CDCL13/CD30D, 1/1) 169.05, 166.66, 148.66, 147.79, 141.99, 135.30, 129.21, 129.02, 128.70, 126.55, 123.51, 121.23, 105.13, 81.39, 42.58, 40.39, 40.09, 36.76, 30.38, 24.95, 17.44, 14.54 and 13, 04 5.

Example 18

( 6R) - 5, 6- dihydro- 4- hydroxysv- 6- r 1-( 2- f envl) etvn- 6- propvl- 2H-pyran- 2- one fCVI)

(R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, (IR,2S)-norephedrine salt (CIV, 180 g; 486 mmol) is converted to (R)-3-hydroxy-3-(2-phenylethyl) hexanoic acid by suspending the salt in methylene chloride (1100 ml) and adding hydrochloric acid (2 M,

720 ml), the free acid is extracted with methylene chloride, and the mixture is dried azeotropically by atmospheric distillation with stepwise addition of methylene chloride (700 ml in total). The free acid mixture (350 mL) is added to a slurry of carbonyldiimidazole (90.5 g, 558 mmol) in methylene chloride (80 mL) and pyridine (210 mL) at -10 to 0 °C. The mixture is heated to

0 °C and stirred for 1 hour.

A slurry of malonate monoethyl ester magnesium salt is prepared by adding an acetone slurry of potassium malonate monoethyl ester (144 g, 846 mmol in 350 mL acetone) to a slurry of magnesium chloride (72 g, 756 mmol) which has been prepared by slowly adding acetone (250 mL) to a slurry of magnesium chloride in methylene chloride (100 ml). The preparation of the malonate salt is completed by atmospheric distillation to a volume of 350 ml.

The (R)-3-hydroxy-3-(2-phenylethyl)hexanoyl imidazo mixture from the carbonyldiimidazole activation is added to the magnesium ethyl malonate slurry at 10-20 °C. The mixture is heated to 20-25 °C and stirred for approx. 16 hours. The reaction

quenched by the addition of hydrochloric acid (5 N, 850 ml). Methylene chloride (125 ml) is added and the phases are separated. The product-containing organic layer is washed with hydrochloric acid (1 N, 400 ml) and then with saturated sodium bicarbonate solution (500 ml). The organic phases are concentrated under vacuum to approx. 200 ml, methanol (700 ml) is added and the vacuum concentration is continued to a final volume of 150 ml. To the methanolic solution of (R)-ethyl-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoate is added a methanolic solution of potassium hydroxide (59.5 g, 85%; 902 mmol dissolved in 200 ml methanol) at 15-20 °C. The mixture is stirred for 16 hours at 20 °C. Water (350 ml) is added and the product-containing aqueous layer is washed twice with methyl t-butyl ether (350 ml for each wash). The aqueous phase is acidified with hydrochloric acid (6 M, 220 ml), and the product is extracted with toluene (550 ml). The toluene mixture is washed with water (150 ml) and concentrated under reduced pressure to 200 ml. The product is crystallized by adding branched octane (approx. 400 ml in two portions that allow crystallization between the additions). On cooling, the product is isolated by vacuum filtration, washed with branched octane and dried at 20-25 °C to give the title compound.

Example 19

5. 6- dihydro- 4- hydroxy- 6- r1-(2- f 4- substituted) phenyl) etvl1- 6- isopropyl- 2H- pyran- 2-one (CVI)

By following the general procedures of Examples 1-4 and performing non-critical variations, but starting with 4-hydroxy-, 4-amino-, 4-monoalkylamino- or 4-dialkylamino-phenyl-2-methyl-3-pentanone (CI), the title compound is obtained.

Example 20

1 6S)- 5. 6- dihydro- 4- hydroxy- 6- r W 2- phenyl) etvl1- 6- phenvl- 2H-pyran- 2-one fCVI)

By following the general procedure of Examples 1-4 and performing non-critical variations, but starting with 1,3-diphenyl-1-propanone (CI), the title compound is obtained.

Example 21

t-butyl-3-hydroxy-3-(2-phenylethylhexanoate (II)

By following the general procedure of Example 1 and making non-critical variations, but using t-butyl acetate instead of ethyl acetate, the title compound is obtained. It is preferred that t-butyl acetate is used.

Claims (25)

1. Connection, characterized in that it is (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid (IV), and pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, characterized in that the pharmaceutically acceptable salts are selected from the group consisting of hydroxide, ammonia, tromethamine (THAM), 2-amino-2-(hydroxymethyl)-1,3-propanediol, (IR,2S) -norephedrine, (IS,2R)-norephedrine, (R)-2-amino-2-phenylethanol, (S)-2-amino-2-phenylethanol, (R)-l-phenyl-ethylamine and (S)-l -phenylethylamine. 3. Compound according to claim 1, characterized in that it is (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, (IR,2S)-norephedrine salt. 4. (6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2-one. 5. [ 3ot(R),6(R)]-5,6-dihydro-4-hydroxy-3-[l-(3-nitrophenyl)propyl]-6-[l-(2-phenyl)ethyl]- 6-propyl-2H-pyran-2-one (XVII). 6. (S)-Methyl 3-(3-nitrophenyl Jpentanoate). 7. [3α(R),6(R)]-5,6-dihydro-4-hydroxy-3-[(Z)-1-(3-nitrophenyl)propenyl]-6-[1-(2-phenyl) )ethyl]-6-propyl-2H-pyran-2-one. 8. Procedure for the preparation of the hydroxylactone of formula (CVI) where Ri is: Ci-Ce alkyl, cyclohexyl, phenyl, -CH2-CH2-<t>Ri-1 / where Ri_i is -OK (and protected forms thereof), -NH2 (and protected forms thereof), - H, -NH-CO-CH3, -N(-CO-CH3)2; where R2 is: Ci~C6-alkyl, cyclohexyl, phenyl, -CH2-CH2-+R2-1, where R2-1 is -OH (and protected forms thereof), -NH2 (and protected forms thereof), - H, -NH-CO-CH3, -N(-CO-CH3)2; characterized in that it comprises: (1) a salt of formula (CIV) is contacted with an acid to produce a free acid, (2) the free acid is extracted from the reaction mixture, (3) the free acid is contacted with an activator, (4) the free acid/activator reaction mixture is contacted with malonate monoester and a divalent metal, (5) contacting the reaction mixture from step (4) with an acid, (6) contacting the reaction mixture from step (5) with a base in the presence of a C 1 -C 4 alcohol, THF or DMF. 9. Process for producing the hydroxylactone with formula (CVI) according to claim 8, characterized in that the acid in step (1) is an inorganic acid or an organic acid. 10. Process for producing the hydroxylactone with formula (CVI) according to claim 8 or claim 9, characterized in that the extraction of the free acid is carried out with a non-polar, organic solvent. 11. Method according to claim 10, characterized in that the non-polar, organic solvent is selected from methylene chloride, toluene, benzene, methyl acetate, ethyl acetate, methyl tert-butyl ether, ethyl ether and hexane. 12. Process for producing the hydroxylactone with formula (CVI) as defined in claim 8, characterized in that it comprises: (1) the anion with formula (CIV) as defined in claim 8 or the free acid form thereof is brought into contact with an activating agent , (2) contacting the free acid/activator reaction mixture with malonate monoester and a divalent metal, (3) contacting the reaction mixture from step (2} with an acid, (4) contacting the reaction mixture from step (3) with a base in the presence of a C1-C4 alcohol, THF or DMF. 13. Method according to any one of claims 8-12, characterized in that the activating agent is carbonyldiimidazole, 14. Method according to any one of claims 8-13, characterized in that the contact with an activating agent is carried out in the presence of a base. 15. Method according to claim 14, characterized in that the base is selected from pyridine, 4-N,N-dimethylaminopyridine, dimethylaniline, diethylaniline, 2,6-lutidine, triethylamine, tributylaraine and collidine. 16. Method according to any one of claims 8-15, characterized in that the malonate monoester is K0-C0-CH2-CO-0-Re, where Re is C1-Cj-alkyl or phenyl. 17. Method according to claim 16, characterized in that the malonate monoester is the C1 or C2 ester. 18. Method according to any one of claims 8-17, characterized in that the divalent metal is <Mg2+,> Ca<2+> and Zn2+. 19. Method according to claim 18, characterized in that the divalent metal is Mg<2+>. 20. Method according to any one of claims 8-19, characterized in that the acid in the penultimate step is an inorganic acid or an organic acid. 21. Method according to any one of claims 8-20, characterized in that the acid or both acids are selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen bromide, hydrogen iodide, citric acid, trifluoroacetic acid, chloroacetic acid, sodium hydrogen sulfate and potassium hydrogen sulfate. 22. Method according to any one of claims 8-21, characterized in that the base in the last step is an organic base or an inorganic base. 23. Method according to claim 22, characterized in that the base is selected from hydroxide, C 1 -C 4 alkoxide and carbonate. 24. Method according to any one of claims 8-23, characterized in that the excess of malonate monoester is removed by extraction before the next step. 25. Method according to claim 24, characterized in that the extraction comprises the use of a base selected from hydroxide, tertiary amines, carbonate and bicarbonate.